TW200305410A - Derivatives of α -phenylthiocarboxylic and α -phenyloxycarboxylic acids useful for the treatment of diseases responding to PRAR α activation - Google Patents

Abstract

Formula (I) compounds are described, in which the substituents have the meanings described in the text, and which are useful for the treatment of diseases responding to PPAR α activation, such as heart failure, the hyperlipaemias and atherosclerosis.

Description

200305410 (1) 说明. Description of the invention The technical field to which the invention belongs The invention described herein relates to the general formula (I) which can be used to treat diseases that respond to the activation of PPAR α (peroxisome proliferator-activated receptor ^). ) Of α-phenylthiocarboxylic acid and α-phenoxycarboxylic acid derivatives:

(I) wherein: R represents -Η, -YCR5R6COX, which may be substituted with one or more -YCR5R6COX, halogen, nitro, hydroxyl, alkyl, and alkoxy which may be substituted with one or more halogen groups Monocyclic, bicyclic or tricyclic aryl or heteroaryl, in which it is possible to use aryl or heteroaryl with one or more -YCR5R6COX, halogen, nitro, hydroxy, alkyl and possibly with one or more Halo-substituted alkoxy-substituted monocyclic, bicyclic, or tricyclic aralkyl or heteroaralkyl, wherein the heteroaryl may be charged, as shown in the following formula ...

The positive charge is balanced by a suitable negative counter ion; m represents 0 -1; (2) (2) 200305410 η represents 0-3; when η represents 1, r3 and R4 may be the same or different, and are selected from Η Or alkyl c ^ C 5; when η represents 2 or 3, then R3 is the same as R4 and represents Η; P represents 〇-1, X represents -0Η, -0-alkyl C "C3; R1 and R2 may be the same Or different, selected from: -η; alkyl Ci- alkoxy which may be substituted with one or more halogen groups; phenoxy which may be substituted with one or more halogen, nitro, hydroxyl, alkyl groups A benzyloxy group substituted by one or more _ prime, nitro, hydroxy, alkyl; _cox; or $ R2 and COX of the general formula (丨) form a ring of the following type:

R5 and R6 may be the same or different 'is selected from the δ group defined by ri and R2;

Q and Z may be the same or different and are selected from: ν η, 〇, S, _ NhlC (〇) 0-, NHC (O) NH-, -NHC (〇) S-, -0C (〇) NH- _NHC (S) 0_, _NHC (S) NH-, -C (0)

NhU: and ya represent 0, s. Diseases that respond to PPARa activation as described herein Heart failure, hyperlipidemia, and atherosclerosis. (3) (3) 200305410 Prior art PPARs, members of the nuclear receptor subgroup, are transcription factors that regulate the activation of ligands for gene expression. Various PPAR isoforms have been proven: PPARa, PPAR 5 (sometimes expressed as / 3) and PPARr ("· Med. Chem. 2000, 43, 527-550; Nature 2000, 405, 421-424) 〇PPAR α Belongs to a large group of steroid hormone receptors (Kersten et al. Nature 2000, 405: 421-424) 〇 This receptor was originally used to control the oxidation of fatty acids against peroxisome proliferators (such as fibric acid derivatives) The receptor was confirmed based on the gene encoding of the enzyme (Issemann and Green, Nature 1990, 347: 645-650).

Proc. Natl. Acad. Sci. USA 1 999, 96: 7473-7478 by Leone et al. Confirmed that PPAR alpha plays a key fatty acid role in tissues. Heart failure is an important cause of inability and sudden death. Due to heart failure, the amount of blood pumped is insufficient to meet the metabolic needs of various tissues. This symptom, along with a control system that enables the electrical and mechanical functioning of the heart, has completely changed. The discovered biochemical and neurohormonal abnormalities constitute a mechanism that adapts to the alteration of the cardiovascular system of the decompensated heart. It is mainly characterized by reduced cardiac output, increased resistance to peripheral heart failure and retention of upstream blood, resulting in arterial expansion and retrograde. Decompensation. The pathophysiological mechanisms involved in the attack, occurrence and progression of heart failure still require some degree of clarification. -9-(4) (4) 200305410 Compounds known to be useful in treating diseases that respond to PPAR alpha activation. Gen. Pharmacol. 1 995 Sep; 26 (5): 897-904 reported the beneficial effects of etomoxir on cardiac performance and the involvement of PPAR α. In Prostaglandins Leukot. Essent. Fatty Acids; 1999 May-Jun; 60 (5-6): 339-43, a report on the involvement of etomis and P PAR α in lipid metabolism control was reported. In Am. J. Physiol. Renal. Physiol. 2000 Apr; 278 (4): F667-75, a report of an etomos-type PPARa activator and a regulation effect of the activation-induced fatty acid oxidation was reported. In Circulation 1 997, 96: 3681-3686 and Br. J. Pharmacol. 1999, 1 26: 501 -507, reports on the effective improvement of myocardial function in animals with hypertrophy and heart failure by etomis have been reported. In Clin. Sci. (Colch) 2000; Jul .; 99 (1): 27-35, it is reported that patients with heart failure will improve cardiac function after treatment with etomimus. In Curr. Opin. Lipidol · 1 999, 1 0: 245-247, it is proposed that fibrates stimulate fatty acid oxidation, inhibit vascular wall inflammation, and protect from atherosclerosis with activated PPAR α. Reported. In WO 98/05331 Curr. Opin. Lipidol. 1 999, 1 0: 245-247, it is proposed that activated PPAR α provides fibrates with protective effects against hypertension, coronary artery abnormalities, and atherosclerosis caused by diabetes. The report of -10- (5) (5) 200305410 However, so far, very few compounds have been able to effectively activate pPARα and prove that it can be used to treat cardiac decompensation. In this field of medicine, there is therefore still a strong cognitive need for new and increasingly specific drugs for the treatment of this symptom. The known compounds mentioned above do not have non-specific disadvantages. In fact, Therapie 1991 Sep-Oct; 46 (5): 351-4 suggested that fibrates cause many side effects, such as reports of skin reactions, bleeding, pancreatitis, and neurological abnormalities. In Current Pharmaceutical Design, 1 998; 4: 1-15, it is reported that etomimus induces myocardial atherosclerosis and increases the risk of myocardial infarction. Therefore, there is still a strong cognitive need for the new PPAR α active agent imparted by the above-mentioned disease symptoms, but there are no shortcomings exhibited by the above-mentioned known compounds. He was able to use it to treat diseases that respond to this PPAR alpha activation. Diseases that respond to PPAR alpha activation as described above include heart failure, hyperlipidemia, and atherosclerosis. The objects of the invention described herein include compounds of formula (丨) and their use in the medical field. Reports that patients with heart failure have improved heart function after treatment with etomimus. -11-(6) (6) 200305410 A further object of the present invention described herein includes a pharmaceutical composition comprising as an active ingredient a compound of formula (I) and at least one pharmaceutically acceptable excipient and / Or thinner. A further object of the invention described herein includes the use of a compound of formula (丨) for the preparation of a medicament for treating a disease that responds to the activation of PPAR α, examples of which are heart failure, hyperlipidemia, and atherosclerosis Although not limited to these diseases. Embodiments The present invention is further illustrated by the following examples. General Synthesis A method for synthesizing a compound of formula (丨) is exemplified by the following scheme. Unless otherwise stated, the meanings of the various symbols conform to the meanings indicated in the general formula (I). The hydrolysis step described in Method A can also be applied to other methods. ° (7) 200305410

Method A

2 Hydrolysis L = Leaving group

R

Compounds of the general formula 丨 are reacted with a base (preferably inorganic and preferably sodium hydride) to form a corresponding anion, and then it is reacted with a group including a leaving group (such as chlorine, bromine, iodine, methanesulfonyl, toluene Compounds of the general formula I 丨 丨 (for example, '^ -bromoisobutyric acid 2-methyl Ester) in polar solvents (such as acetonitrile, toluene or dimethylformamide), at a temperature ranging from 10 to 50 ° C (preferably at 25 ° C) for 18 to 48 hours The reaction is a time period within a range to complete the preparation of the compound of the general formula (1). The product thus obtained is carried out using, for example, Na 0 Η or a mixture of, for example, HC 丨 / acetic acid at a temperature ranging from 10 to 100 ° C (preferably at 25 ° C) from 1 hour to 72 hours. Range -13- (8) 200305410 time period (preferably 3 hours) for alkaline or acid hydrolysis, & production &

Corresponds to acid IA. Method B

(I)

Q = 〇, S Χ / έ〇Η Anhydrous and aprotic solvents are used under the traditional conditions of M itsunobu reaction starting with compounds of the general structure IV and the alcohols of the general structure ν (as explained in Synthesis 1 981, 1-28) (Such as benzene, toluene, ether and dihydrotetrahydrofuran are preferred) at a temperature ranging from 10 to 40 ° C (preferably at 25 ° C) and for a period of time ranging from 30 minutes to 72 hours (with 48 Hours is preferred) reaction to complete the preparation of compounds of general formula (丨)

W = 〇, NH, SK = -NCS, -NCO, -0C (0) CI, -COOH Q ^ Ν, Ο, S -14- (9) 200305410 to dissolve in aprotic solvents (for example, toluene, ether, But with four

Hydrofuran is preferred), the general structure VI starts, and then it is possible to add the relevant isocyanate, thioisocyanate or chloromethyl chloride in the presence of an inorganic or organic base (preferably triethylamine in a catalytic amount or stoichiometry). Ester V Μ, and the remaining mixture at a temperature ranging from 10 to 4 crc (preferably at 25 ° C) and a time period ranging from 6 to 72 hours (preferably at 48 hours) Reaction to obtain the compound prepared by this method. If K is equal to COOH, use a 1-3 equivalent ratio (preferably from 1 to 1.5 equivalents) with respect to the base, such as diethylphosphorocyanate, EEDQ, DCC or CDI and the like Or, through acid chloride formation, in organic solvents (such as DMF, CH3CN, CHCb, THF and the like) and at a temperature ranging from 20 to 80 ° C (preferably 25 ° C) Concentration reaction with reaction time ranging from 18 hours to 3 days (preferably 24 hours).

Q = 0, S X different from OH L = leaving group

-15- (10) (10) 200305410 For example, according to the procedure described by Tetrahedron, 1990, 46 (3), 967-978, starting with the product IV and including a leaving group (such as chlorine, bromine, iodine, mesylsulfonyl, Toluenesulfonyl and diazo groups (in the case of diazo groups, divalent germanium acetate dimers are used instead of inorganic bases as catalysts) compounds of the general formula 11 (eg, α-bromoisobutyric acid 2- Methyl ester) in the presence of a base (such as potassium carbonate) and a phase transfer catalyst (such as, for example, tetrabutylammonium bromide (TBBA)) and in an aprotic solvent (such as toluene), from 25 t to the selected solvent The reaction temperature is in the range of 1 to 5 days (preferably 2 days) at a temperature ranging from 1 to 5 to complete the compound of general formula (I) (m and η are equal to 0, Y and Q are equal to 0 and / Or S). Example 1 2- (4-Hydroxyphenylsulfan) methyl isobutyrate (ST1 923) Preparation method A Step 1 Add 80% NaH (0.144 g, 4.8 mmol) 4-mlphenol (0.500 g, 4.0 mmol) in 10 mL of anhydrous CH3CN. The mixture was cooled to 0 ° C and after 5 minutes, added α-Bromoisobutyric acid methyl ester (0.72 4 g, 4.0 mmol). The reaction mixture under magnetic stirring was left at room temperature for 2 days. The reaction mixture was then poured into Η20 and extracted with ethyl acetate. The aqueous phase was then acidified and extracted with ethyl acetate. The aggregated organic phase was dried over Na 2 SO 4, filtered, and evaporated. The obtained residue was purified by a silica gel layer separation method using CHCI 3 as a dissolving agent. 0.760 g of product was obtained (yield: 84%); -16- (11) (11) 200305410 MP (melting point): 1 1 0 -1 12 ° C; TLC: silicone, eluent CHCI3, Fr (frontier ratio) : 0.11; 1H NMR (CDCI3, 300MHz) 5 7.30 (d, 2H), 6.73 (d, 2H), 5.57 (brm '1 Η), 3.70 (s, 3H), 1.45 (s, 6H); HPLC ·· Column: Symmetry-C18 (5 microns) 4.6x250 mm 'R · T. (Room temperature), mobile phase 50/50 (volume / volume) CH3CN / H2〇, pH: constant, flow rate: 0.75 Ml / min, 205 nm UV detector, 10.14 minutes residence time; C11H14O3S was determined by EA (Elemental Analysis). Example 2 2- (4-Hydroxyphenylsulfide) isobutyric acid (ST 1 981) Step 2 of Preparation Method A 2.7 ml of acetic acid and 2.7 ml of 37% hydrochloric acid are added to methyl 2- (4-hydroxyphenylthio) isobutyrate (ST1 923) (0.200 g, 0.88 mmol) Ear), and the mixture thus obtained was left under reflux overnight under magnetic stirring. The solution was then poured into water and the aqueous phase was extracted with ethyl acetate. The organic phase was then dried over Na2S04, filtered and evaporated. Obtained 0.161 g of product (yield: 87%); melting point: 1 52-1 54 t; TLC: silicone, eluent CHCI3 / CH3OH of 9/1, Fr: 0.38; 1 H NMR (DMSO, 300MHz) 5 7.23 (d, 2H), 6.72 (d, 2H), 3.30 (brm, 2H), 1.30 (s, 6H); HPLC: column: Inertisil 〇DS-3 (5 microns) 4.6x250 mm, room temperature The mobile phase is -17- (12) (12) 200305410 CH3CN / KH2P〇4 'at 50/40 50/50 (volume / volume) pH: constant, flow rate: 0.75 ml / min, 205 nm UV detection Tester, residence time 7.39 minutes; KF: 0.5% Η20; determination of CiOH1203S0 by elemental analysis Example 3 Preparation of 2- (3-hydroxyphenylthio) isobutyric acid methyl ester (ST2 047) according to the method A (Step VII). The product was prepared by the procedure described in 40 ml of anhydrous CH3CN with 3-acetol (2,000 g, 15.9 mmol) and 80% NaH (0.572 g, 19.1 mmol) in (TC After 5 minutes, methyl 2-bromoisobutyrate (2.88 g, 1 5.9 mmol) was added to the suspension. The reaction mixture thus obtained was left under magnetic stirring at room temperature overnight. Then reverse The mixture was poured into H20 and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The obtained residue was separated by a silica gel layer using 98/2 CHCI3 / CH3OH as the eluent. Purified. 2.900 g of product (yield: 81%); melting point: 41.5-42.5 ° C; TLC: silicone, eluent: CHCI3 / CH3OH, Fr: 0.2 3; 1 H NMR (CDCI3, 300MHz) 57.19 (t, 1 H), 7.00 (d, 1H), 6.95 (brt, 1H), 6.81 (dd, 1H), 3.69 (s, 3H), 1.50 (s, 6H); HPLC: column:

Inertisil ODS-3 (5 micron) 4.6x250 mm, room temperature, mobile phase 50/50 (vol / vol) CH3CN / H20, pH: constant, flow rate: 0.75 ml / min, 205 nm UV detector , Stay time 13.82 minutes; KF: 0_3% H2O; determined by elemental analysis -18- (13) 200305410 C 1 1 Η 1 4 〇3 s 0 Example 4 2 · 「4- ί 2- (4_chlorophenyl) Ethylhydrogen] Benzothion 1 Litidine p methyl alcohol (ST1929) Preparation

Method B

DEAD (0.801 g, 4.6 mmol) and triphenylphosphine (1.2 05 g, 4.6 mmol) were added in a small amount to maintain the temperature below 30 ° C. 2- ( 4-hydroxyphenylthio) methyl isobutyrate (ST1 923, prepared as described in Example 1) (0.800 g, 3.54 mmol) and 4-chlorophenylethanol (0.554 g, 3.54 mmol) )in. The reaction mixture was left under magnetic stirring at room temperature overnight. The solvent was then evaporated and the residue was purified by silica gel layer separation using 9/1 hexane / ethyl acetate as the eluent. 0.416 g of oily product was obtained (yield: 32%); TLC: silicone, eluent 9/1

Hexane / ethyl acetate, Fr: 0.32; 1H NMR (CDCI3, 300MHz) 5 7.40-7.19 (m, 6H), 6.80 (d, 2H), 4.15 (t, 2H), 3.65 (s, 3H) , 3.08 (t, 2H), [45 (s, 6H); HPLC: column: Symmetry-C18 (5 microns) 4 _ 6x250 mm, room temperature, mobile phase 70/30 (volume / volume) CH3CN / H2〇, pH: unchanged, flow rate: 0.75 ml / min, 205 nm UV detector, residence time 31.40 minutes; KF · 0.4% H2O; C19H21CI03S was determined by elemental analysis. -19- (14) (14) 200305410 Example 5 2_ [1-Di. [-Indole] Ethylarginyl] phenylthioanine methyl butyrate (ST.H.8U Preparation 1-(?- Μ) Preparation of the indole intermediate product D. The intermediate product reported therein was prepared according to the procedure described in J. Med. Chem. 1998, 41/10, 1619-1639, except for the reaction time period (with 30 hours instead of 30 minutes), indole (5.0 g, 42.7 mmol), KOH (3.6 g, 64.1 mmol) and bromoethanol (6.4 g, 51.3 mmol) in 50 ml of anhydrous DMSO ) Starting at T: 25-30 ° C, 5 g of oily product is obtained (yield: 73%) 〇-20- 1 [2- (1-indolyl) ethoxy] phenylthio 1-litin Methyl ester "_ $ T1 983) Preparation The product was prepared according to the procedure described in Method B, and 2- (cardiohydroxyphenylthio) in 15 ml of anhydrous THF was added in a small amount to maintain the temperature below 30 ° C. ) Methyl isobutyrate (ST1 923, prepared as described in Example 1) (0.671 g, 2.97 mmol), 1- (2-hydroxyethyl) indole (0.478 g, 2.97 mmol), DEAD (0.672 g, 3.86 mmol) and three Phenylphosphine (1.011 g, 3.86 mmol) was started. The reaction mixture under magnetic stirring was left at room temperature for 48 hours. The solvent was then evaporated and the residue was purified by silica gel layer separation using 8/2 hexane / ethyl acetate as the eluent. A total of 0.500 g of still impure product was obtained, which was dissolved in ethyl acetate and washed with a solution of (15) (15) 200305410 equivalent NaOH. The organic phase was dried and evaporated to produce a residue of 0 2 230 g, which was further purified by a silica gel chromatography using C H C 3 as a dissolving agent. Obtained 0.184 g of oily product (yield: 17%); TLC: silicone, 8/2 hexane / ethyl acetate, Fr: 0.29; 1H NMR (CDC 13, 30 0 MHZ) 5 7.62 (d, 1Η), 7.40-7.10 (m, 6Η), 6.78 (d, 2Η), 6.50 (d, 1Η), 4.50 (m, 2H), 4.24 (m, 2H), 3.61 (s, 3H), 1.40 (s, 6H); HPLC: column: Symmetry-

Ci8 (3.5 micron) 4.6x75 mm, room temperature, mobile phase 60/40 (vol / vol) CH3CN / H20, pH: constant, flow rate: 0.90 ml / min, 205 nm UV detector, residence time 1 0.70 minutes; KF: 1.7% Η20; c2iH23N03S was determined by elemental analysis. Example 6 Preparation of 2-[_ 4- [2- (2-naphthyl) ethoxy] phenylthio] isobutyrate (ST2011) The product was prepared according to the procedure described in Method B to keep the temperature low Add methyl 2- (4-hydroxyphenylthio) isobutyrate (ST1 923, prepared as described in Example 1) in 30 ml anhydrous THF in small amounts (1.000 g, 4.42 mmol) Ear), 2- (2-naphthyl) ethanol (0.760 g, 4.42 mmol), DEAD (1.000 g, 5.75 mmol) and triphenylphosphine (1.500 g, 5.75 mmol). The reaction mixture under magnetic stirring was left at room temperature overnight. The solvent was then evaporated and the residue was purified by silica gel layer separation using 9/1 hexane / ethyl acetate as the solvent -21-(16) (16) 200305410. 1 2 6 2 g of product was obtained (yield: 7 5%): melting point: 5 6-5 7 ° C; TLC: silicone, eluent based on 9/1 hexane / ethyl acetate, Fr: 0.23; 1H NMR ( CDCI3, 300ΜΗζ) ά 7.8 5-7 · 7 0 (m, 4 Η), 7 · 4 5-7 · 2 8 (m, 5 Η), 6 · 8 3 (d, 2H), 4.27 (t, 2H ), 3.65 (s, 3H), 3.26 (t, 2H), 1.45 (s, 6H); HPLC: column: Inertisil ODS-3 (5 microns) 4.6x250 mm, room temperature, mobile phase series 80/20 ( Volume / volume) of CH3CN / H20, pH: constant, flow rate: 0.75 ml / min, 2.5 nm UV detector, residence time 2 3 · 5 1 min; KF: 0.16% Η 20; elemental Analysis determined C23H2403S. Example 7 Preparation of 2- [4- (2- (naphthyl) ethoxy]] phenylthio]] isobutyric acid (ST2036) 12.9 ml of 1 equivalent of NaOH was added to ST201 1 in 30 ml of methanol (eg (Illustrated in Example 6) (0.489 g, 1.29 mmol) in solution. The solution thus obtained was left at reflux overnight. The solution was then cooled, diluted with water and acidified, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried over anhydrous Na2S04, then evaporated in vacuo and the residue was purified by silica gel layer separation using chloroform as the eluent. 0.360 g of product was obtained (yield: 76.2%); melting point: 103-104 ° C; TLC: silicone, eluent: CHCI3 / CH3OH, 98/2, Fr: 0.13; 1 H NMR (CDCI3, 300MHz) 5 7.80 (m , 3H), 7.70 (s, 1H), 7.50-7.38 (m, 5H), 6.83-22- (17) (17) 200305410 (d, 2H), 4.26 (t, 2H), 3.35 (t, 2H) , 1.48 (s, 6H); HPLC: column: Inertisil ODS-3 (5 micron) 4.6x250 mm, room temperature, mobile phase 75/25 (vol / vol) CH3CN, KH2P04, pH: constant, flow rate : 0.75 ml / min, 205 nm UV detector, dwell time 彳 3.07 minutes; KF: 1% H20; C22H2203S was determined by elemental analysis. Example 8 gji 丄 4-[_ [(4-methoxybenzyl) amine formamidine 1 gas a] benzene sulfur

Group] methyl isobutyrate (ST2031). Preparation method C. p-methoxybenzyl isocyanate (0.417 g, 2.56 mmol) and 0.010 g of triethylamine were added to ST1923 (0.482 in 10 ml of anhydrous THF). G, 2.13 millimoles) (made as described in Example 1). The solution under magnetic stirring was left at room temperature for 48 hours. After this time period, the solvent was evaporated and the residue was purified by a silica gel layer separation method using 98/2 CHCI3 / CH3OH as the eluent. 0.41 0 g product (yield: 50%); melting point: 64-65 ° C; TLC: silicone, eluent CHC 13, Fr: 0.1 4; 1 H NMR (CDCI3, 300 MHz) δ 7.44 (d , 2H), 7.28 (d, 2H), 7.10 (d, 2H), 6.90 (d, 2H), 5.29 (brm, 1H), 4.39 (d, 2H), 3.80 (s, 3H), 3.65 (s , 3H), 1.48 (s, 6H); Η PLC ·· column: | ne rt isi | 〇D S-3 (5 microns) 4.6x250 mm, room temperature 'mobile phase system 7〇 / 3〇 (volume- 23- (18) (18) 200305410 / volume) CH3CN / H20, pH: constant, flow rate · 0.75 ml / min, 205 nm UV detector, residence time 1 1.22 minutes; determined by elemental analysis C2QH23N05S. Example 9 2 · [3- [[(4-methoxybenzyl) amine formamidine]] Hydrogen 1 Benzylsulfide] Isobutyric acid methyl ester (ST21 39) Preparation according to the procedure described in Method C The product was ST2 047 (prepared as described in Example 3) in 7 ml of anhydrous THF (0.240 g, 1.06 mmol), p-methoxyphenylfluorenyl isocyanate (0.2 07 g, 1.27 mmol) ) And 0.010 g of triethylamine, the solution was left to stir at room temperature for 18 hours. Next, 0.086 g (0.53 mmol) of p-methoxybenzyl isocyanate was added, and the mixture under magnetic stirring was left at room temperature for another 6 hours. The solvent was then evaporated to dryness and the residue was purified by silica gel chromatography using 7/3 hexane / ethyl acetate as the eluent. 0.320 g of product was obtained, which was washed with Na 2 C 0 3 for further purification. 0.200 g of oily product was obtained (yield 48%); TLC: silicone, 7/3 hexane / ethyl acetate as eluent,

Fr: 0.3 7; 1 H NMR (CDCI3, 300 MHz) δ 7.35-7.18 (m '6 H), 6.90 (d, 2H), 5.25 (brm, 1 H), 4.40 (d' 2 H), 3.80 (s, 3H), 3.62 (s, 3H), 1.50 (s, 6H); HPLC: column · inertjsil ODS-3 (5 micron) 4.6x250 mm, room temperature, mobile phase 50/50 (volume / (Volume) of CH3CN / H2〇, pH: constant, flow rate: 0.75 ml / min, 205 milli- 24- (19) (19) 200305410 micron UV detector, residence time 47.2 minutes; determined by elemental analysis C20H23NO5S 〇Treasure 1 〇

Preparation of 2- [4- (2-methylamino-1,1-dimethyl-2-2-one ZM) thiothiazine methyl butyrate (ST1 982) D. K2C03 (0.306 g, 2.22 mmol) and tetrabutylammonium bromide (TBAB) (0.0193 g, 0.06 mmol) added to 2- (4-hydroxyphenylsulfanyl) isobutyrate (ST1 923, (Prepared as described in Example 1) (0.250 g, 1.11 mmol); the mixture was heated at 1000 ° C, and after 5 minutes, methyl 2-bromoisobutyrate (0.803 g , 4.44 millimoles ·). The mixture was then left under reflux for 2 days (1 30t oil bath temperature). The mixture was then filtered and the solid was washed with toluene. The pooled organic phase was dried, and the oily residue was dissolved in ethyl acetate and washed with 1 equivalent of NaOH. The residue obtained after evaporating the organic solvent was purified by a silica gel layer separation method using 9/1 of hexane / ethyl acetate as a eluent. Obtained 0.1 45 g of oily product (yield: 40%); TLC: silicone, eluent 9/1 hexane / ethyl acetate, Fr: 0.17; 1H NMR (CDCI3, 300MHz) 57.31 (d, 2H), 6.74 (d, 2H), 3.75 (s, 3H), 3.65 (s, 3H), 1.60 (s, 6H), 1.45 (s, 6H); HPLC: column ... Symmetry-C18 (3.5 microns) 4 · 6 × 75 mm, room temperature, mobile phase 50/50 (volume / volume) -25- (20) (20) 200305410 CH3CN / H2〇, pH: constant, flow rate: 0.75 ml / min, 205 nm UV detection Detector, dwell time 1 3.00 minutes; C16H22O5S was determined by elemental analysis. Example 11 2- [3- [2- (3-Hydroxyammonium) ethane gas] Phenoxyl] Pyrene butyrate (ST1877) and 2- [3- [2- f 3- Γ2 -methoxy-1,1-dimethyl-2-one ethyl ethane] oxy] ethoxy argon 1 methyl isobutyrate ( ST1878) The code was prepared according to the procedure described in Method D to 3,3-ethylenedioxyphenol (2.000 g, 8.1 mmol) in 1000 ml of toluene, K2C03 (4.500 g, 32.4 millimoles), TBAA (0.131 g, 0.4 millimoles), and methyl 2-bromoisobutyrate (11.611 G, 64 mmol) starts. The reaction mixture was heated at 130 ° C for 3 days, then cooled and filtered. The obtained solid was washed with toluene, the collected organic phase was evaporated to dryness in a vacuum, and the oily residue was purified by a silica gel layer separation method using 8/2 hexane / ethyl acetate as a eluent. Two products were obtained: a single derivative ST1877 (0.700 g) (yield: 25%) and a second derivative ST1 878 (1.0 g) (yield: 3 0.4%). Analytical data of ST1 877 Melting point: 77-79 ° C; 1H NMR (CDCI3, 300MHz) 5 7.13 (t, 2H), 6.62-6.40 (m, 6H), 4_25 (s, 4H), 3.78 (s, 3H) , 1.60 (s, 6H); HPLC: column: -26- (21) 200305410 13-26 chamber in the flow chamber for production test.

Inertisil ODS-3 (5 microns); 4 · 6x2 50 mm, room temperature, phase-shifting CH3CN / H20 (60/40 (vol / vol)), pH: 3.2, speed: 1.0 ml / min, 205 nm UV Detector, 8.76 minutes on stay; C19H2206 was determined by elemental analysis. Analytical data of ST1 878 Melting point: 60-62 ° C; 1H NMR (CDCI3, 300MHz) δ Ί. (T, 2Η), 6.60 (d, 2H), 6.41 (m, 4H), 4.

(s, 4H), 3.78 (s, 6H), 1.60 (s, 12H); HPLC column: Inertisil ODS-3 (5 microns); 4.6x250 mm, temperature, mobile phase system CH3CN / H20 (60/40 ( Volume / volume)) ρ: 3.2, flow rate: 1.0 ml / min, 205 nm UV detector, residence time 23.92 minutes; C24H3Q08 was determined by elemental analysis. Example 1 2. [4- [1- (4-Hydroxybenzene-1) -1-methylethyl-1 1phenylchloro-1] malonic acid diester (ST2020) Prepared according to the following steps as described in Step 1 of Method A: A solution of 50 ml of diazomalonate in anhydrous toluene (2.846 g, 18 mmol) (as prepared by Org. Synth ·: 1973, V, 179) was added dropwise under a stream of nitrogen at 100 Suspension of divalent rhodium acetate dimer (0.220 g, 0.5 mmol) and phenol A (2,2-bis (4-hydroxyphenyl) propane) (3.4 00 g, 15 mmol) in anhydrous methyl chloride In the liquid, carefully maintain the temperature between 15 and 20 ° C. The reaction mixture was refluxed under nitrogen at 120 to 30 ° C for 24 hours. -27- (22) (22) 200305410 The reaction mixture was filtered and the toluene was evaporated in vacuo. The obtained residue was purified by silica gel chromatography using 8/2 hexane / ethyl acetate as a eluent. 1_700 g of oily product was obtained (yield: 32%); TLC: silicone, eluent was 7/3 hexane / ethyl acetate,

Fr: 0.23; 1H NMR (CDCI3, 300MHz) 57.16 (m, 4H), 6.90 (d, 2H), 6.87 (d, 2H), 5.12 (s, 1H), 3.90 (s, 6H), 1.62 (s, 6H); HPLC: column:

Inertisil ODS> 3 (5 micron) 4.6x250 mm, room temperature, mobile phase 70/30 (vol / vol) CH3CN / H20, pH: constant, flow rate: 0.75 ml / min, 205 nm UV detector , Staying time 7.00 minutes; KF: 0.6% Η 20; c2qH22〇6 determined by elemental analysis. Example 1 3 L [4- (1-{4- [2 -methoxy-1-(methoxycarbonyl-1) -2-one ethyl argon a certain phenyl phenyl 1-methylethyl) phenoxy a certain propane Dimethyl acid (ST2048) was prepared according to the procedure already described in Example 12, as described in Step 1 of Method A, to a divalent rhodium acetate dimer (0.0885 g, 0.2 mmol) in 36 ml toluene. Mol) and ST2 02 0 (1.230 g, 3.4 mmol) (prepared as described in Example 12), diazomalonate (1.882 g, 1 1 · 9 millimoles), taking care to maintain a temperature between 15 and 2 CTC. The reaction mixture was refluxed under nitrogen at 120-130 ° C for 24 hours. The reaction mixture was then filtered and the toluene was evaporated in vacuo. The obtained residue -28- (23) (23) 200305410 was purified by a silica gel layer separation method using 8/2 hexane / ethyl acetate as a eluent. 0.430 g of an oily product was obtained (yield: 26%); TLC: silicone, eluent: 6/4 hexane / ethyl acetate, Fr: 0.46; 1 H NMR (CDCI3, 300MHz) 5 7.20 (d, 4H) , 6.90 (d, 4H), 5.22 (s, 2H), 3.90 (s, 12H), 1.61 (s, 6H); column: Inertisil ODS-3 (5 microns) 4.6x2 50 mm, room temperature, mobile phase 70/30 (vol / vol) CH3CN / H2〇, pH: constant, flow rate: 0.75 ml / min, 205 nm UV detector, dwell time 9.68 minutes; KF ·· 0.7% H2O; elemental analysis Determine C25H28O10. Example 1 4 U .._ 3: [2- (2-naphthyl) ethoxy] phenylsulfanyl methyl methyl butyrate "ST2167) Preparation The product was prepared according to the procedure described in Method B (except for the replacement of DEAD with DIAD Other than), methyl 2- (3-hydroxyphenylthio) isobutyrate (ST2047) (1.1 10 g, 4.9 mmol), 2- (2-naphthyl) in 20 ml of anhydrous THF Ethanol (0.842 g, 4.9 millimoles), DIADC 1.290 g, 6.37 millimoles) and triphenylphosphine (1.67 0 grams' 6.37 millimoles) started. The reaction mixture under magnetic stirring was left at room temperature overnight. The solvent was then removed under vacuum and the residue was purified by silica gel layer separation using 7/3 hexane / ethyl acetate as the eluent. The product was dissolved in ethyl acetate and the organic phase was washed with Na2C03 solution 'to further purify it. The organic phase was then dried over anhydrous sodium sulfate. -29- (24) (24) 200305410 was dried 'filtered and the solvent was evaporated in vacuo. 1.14 g of product was obtained (yield: 61.2%); TLC: silicone, eluent 9/1 hexane / ethyl acetate, Fr: 0 · 20; 1H NMR (CDCI3, 300 MHz) 57.80 (m ' 3H), 7.75 (s, 1H), 7.45 (m, 3H), 7.25 (t, 1 H), 7_05 (m, 2H), 6.90 (d, 1 H), 4.25 (1 '2H), 3.65 (s , 3H), 3.30 (t, 2H), 1.50 (s, 6H); HPLC: column: Inertisil 〇DS-3 (5 microns) 4 · 6x250 mm, room temperature, mobile phase system 80/20 (vol / vol) ) Of CH3CN / H2O, pH: constant, flow rate: 0.9 ml / min, 205 nm UV detector, residence time 18.91 minutes; KF: 1.0% H2O; C23H2O3S was determined by elemental analysis. Example 1 Preparation of 5 h [3-i Γ [4- (trifluoromethyl) benzene] amine methylamidino] oxy 1 melanyl] isoT acid methyl ester (ST2208) according to the steps described in Method C The product was prepared with ST2 047 (0.800 g, 3.54 mmol) (prepared as described in Example 3), 4-trifluoromethyl isocyanate (0.749 g, 4.25 mmol) in 10 ml of anhydrous THF. And 〇 〇〇〇10 grams of triethylamine started, the reaction time is 18 hours at room temperature instead of 48 hours. The solvent was then evaporated to dryness and the residue was purified by silica gel chromatography using CHCI3 and 98/2 CHCI3 / MeOH as eluents. 0.881 g of product was obtained (yield = 60%); melting point = 66-67 ° C; TLC: silicone, eluent CHCI3, Fr: 0.38; 1H NMR (CDCI3, 300MHz) 5 7.60 -30- (25) (25) 200305410 (m, 4H), 7.38 (m, 3H), 7.15 (m, 1H) »7.06 (brs, 1H), 3.70 (s, 3H), 1.55 (s, 6H); HPLC: column: Inertisil ODS- 3 (5 microns) 4_6x250 mm, room temperature, mobile phase is 50 mg molecular weight cH3CN / KH2P〇4 (60/40 (volume / volume)), ρ: 3.0 (85% Η3ΡΟ4), flow rate: 1 ml / Minutes, 205 nm UV detector, dwell time 25.46 minutes; KF: 2.5% Η 2〇; C19H18F3NO4S determined by elemental analysis Instance 1 6 ([[[__4 bis (trifluoromethyl) benzylamine formamidine Preparation of argon methyl phenylthio] isobutyrate (ST2209) The title product was prepared according to the procedure described in Method C to ST1923 (0.300 g, 1.33 mmol) in 7 ml of anhydrous THF (eg Prepared according to the description of Example 1), 4-trifluoromethyl isocyanate (0.298 g, 1.6 mmol) and 0.010 g of triethylamine. The reaction time is 18 hours instead of 48 hours at room temperature. The solvent was evaporated to dryness and the residue was purified by silica gel chromatography using 7/3 of hexane / AcOEt as the eluent. 0.340 g of product (yield: 62%): melting point = 1 1 0-1 1 1 ° C; TLC: Silicone, eluent chci3, Fr: 0.34; 1 Η NMR (CDCI3, 300MHz) (5 7.55 (m, 4Η), 7.48 (d, 2Η), 7.15 (d, 2Η) 5 7.10 (brs, 1 Η), 3_70 (s, 3Η), 1.55 (s, 6H); HPLC: column: Inertisil 0DS-3 (5 microns) 4.6x250 milli-31-(26) (26) 200305410 ^ 'Dish' mobile phase is 50 mg of CH3CN / KH2P04 (60/40 (vol / vol)), pH: 3.0 (85% H3P04), flow rate · 1 stroke / min, 2 〇5 nm UV detector, dwell time 25.60 minutes; C19H18F3N04S was determined by elemental analysis. Example 1 7 ^ [3- [2 Diphenyls) 7, oxyl] phenylthio]] isobutyric acid methyl ester 丄 3 τ 2 1 9 5 Preparation According to the procedure described in Method B, the title product was prepared in 1 5 2- (3-Hydroxyphenylthio) isobutyric acid methyl ester (ST2 047 'as prepared in Example 3) in anhydrous THF (1.0 g, 4.42 mmol) and 4-chlorobenzene Starting with ethanol (0.692 g, 4.42 mmol), add DIAD (1.16 g, 5.75 mmol) and triphenylphosphine (1.500 g, 5.75 mmol) in small amounts to maintain the temperature below 30 ° C. among them,. The reaction under magnetic stirring was left at room temperature overnight. After this period, the solvent was evaporated and the residue was purified by silica gel chromatography using 9/1 hexane / AcOEt as the eluent. Obtained 1.146 g of oily product (yield: 71%); TLC: silicone, eluent 9/1 hexane / AcOEt, Fr: 0 · 28; 1H NMR (CDCI3, 300MHz) 57.25 (m, 6H), 7.00 (m, 1H), 6.90 (d, 1H), 4.15 (t, 2H), 3.65 (s, 3H), 3.08 (t, 2H), 1.55 (s, 6H); HPLC: column: Inertisil ODS 3 (5 microns) 4.6x250 mm, room temperature, mobile phase 80/20 (vol / vol) CH3CN / H20, pH: constant, flow rate: -32- (27) (27) 200305410 〇_ 75ml / Min, 205 nm UV detector, dwell time 19.34 minutes; KF: 1.7% Η20; c19H21CI03S determined by elemental analysis. Example 1 Preparation of 8 g- JL.3- [2- (1 -D Indolyl) ethoxy, 1 sulfan, 1 methylbutyrate (ST2394). The title product was prepared according to the procedure described in Method B. 2- (3-Hydroxyphenylthio) isobutyric acid methyl ester (ST2047, prepared as described in Example 3) in 20 ml of anhydrous THF (1.00 g, 4.42 mmol) and 1-(2- Hydroxyethyl) indole (prepared as described in Example 5) (0.711 g, 4.42 mmol) starting with [) IAD (1.16 g, 5.75 mmol) and triphenylphosphine (1.500 g, 5.75 mmol) Moore) is added in small amounts to maintain the temperature below 30 ° C. The reaction under magnetic stirring was left at room temperature overnight. The solvent was then evaporated to dryness and the residue was purified by silica gel chromatography using 8/2 hexane / AcOEt as the eluent. 0.58 1 g of oily product was obtained (yield: 35%); TLC: silicone, eluent 9/1 hexane / AcOEt, Fr ·· 0.22; 1 H NMR (CDCI3, 300MΗζ) δ 7.62 (d ^ 1 H ), 7.42 (d, 1H), 7.30-6.80 (m, 7 H), 6.52 (d, 1H), 4.55 (m, 2H), 4.30 (m, 2H), 3.61 (s, 3H), 1.50 (s '6H); HPLC: column: Supelco-C18 (5 micron) 4.6x1 50 mm' room temperature, mobile phase 70/30 (vol / vol) CH3CN / H20, pH: constant, flow rate: 0.90 Ml / min, 2.5 nm UV detector, dwell time 6.36 minutes; C21H23NO3S was determined by elemental analysis-33- (28) (28) 200305410. Example 1 9 Preparation of 2- [3-[(1-methyl-1-methylamino) ethoxy] phenylthiophene] isobutyric acid methyl ester (ST24 1 8] was prepared according to the procedure described in Method D. The title product is methyl 2- (3-hydroxyphenylthio) isobutyrate (ST2047, prepared as described in Example 3) in 100 ml of toluene (0.870 g, 3.85 mmol), K2C03 (1.06 g, 7.7 mmol), TBAB (0.06 2 g '0.19 mmol) and methyl 2-bromoisobutyrate (2.8 g, 15.4 mmol) were started. The reaction mixture was at 1 Heated at 30 ° C for 3 days, followed by cooling and filtering. The obtained solid was washed with toluene, the collected organic layer was evaporated to dryness in vacuo and the oily residue was used with 9/1 hexane / AcOEt Purified by silica gel layer separation method as eluent. 彳 .g grams of oily product (yield: 79%); TLC: silica gel, eluent 9/1 hexane / AcOEt, Fr: 0.20; 1 Η NMR ( CDC 13, 3 00 Μ Η ζ) 5 7.20 (m, 1H), 7.05 (d, 1H), 6.95 (s, 1H), 6.90 (d, 1H), 3.80 (s, 3H), 3.65 (s, 3H ), 1.60 (s' 6H), 1.45 (s 6 H); HPLC: column: Symmetry- C18 (5 micron) 4.6x150 mm, room temperature, mobile phase 60/40 (vol / vol) CH3CN / H20, pH: constant, flow rate: 0.75 ml / min '' 205 nm UV detector with a residence time of 9.53 minutes; C 4 6 Η 2 2 0 5 S was determined by elemental analysis. -34- (29) (29) 200305410 Example 20 2- [4- [2- (4 -Chlorin) Ethyl chloride] Bensulfurin -2-Preparation of methylpropionate (ST2505) The title product was prepared according to step 2 of General Method A to ST1 929 in 36 ml of methanol (such as Starting from the solution of Example 4) (0.572 g, 1-57 mmol), 15.7 ml of 1 equivalent of NaOH was added to it. The solution thus obtained was refluxed overnight. The solution was then cooled, diluted with water and acidified. The aqueous phase was extracted with AcOEt. The organic phase was evaporated in vacuo and the residue was purified by silica gel chromatography using 7/3 hexane / AcOEt as the eluent. 0.448 g of product was obtained (yield: 81% ); Melting point = 87-88 ° C; Ding1 _ (:: silicone, eluent system 6/4 hexane / 800 £ 丨, 卩: 0.30; 4 NMR (CDCI3, 300MHz) 5 7.45 (d, 2H), 7.15 (m, 4H), 6_85 (d, 2H), 4.15 (t, 2H), 3.05 (t, 2H), 1.50 (s, 6H); HPLC: column: Symmetry- C18 (5 microns) 4.6x2 50 mm, room temperature, mobile phase is 45 mg / volume (volume / volume) CH3cN / ammonium acetate with a molecular weight of 45 mg / volume, pH: constant, flow rate: 0.70 ml / min, 205 nm (JV detector, dwell time 4.73 minutes; elemental analysis to determine ci8h19ci03s. Example 2 1 1 2. [3. [-4-nitrophenyl) furfuryl 1] phenylthio, critin, butylate ester 1 (-S.T25 01) Preparation of the title product according to the procedure described in Method B, with 2- (3-Hydroxyphenylthio) isobutyric acid methyl ester (ST2047, prepared as described in Example 3) in 23 milli-35- (30) (30) 200305410 liters of anhydrous THF (1.02) Grams, 4-5 millimoles) and 5- (nitrophenyl) furfuryl alcohol (0.986 grams, 4.5 millimoles), starting with 0 丨 80 (1.18 grams, 5.85 millimoles) and triphenylphosphine (1.53 grams, 5.85 MM) was added in a small amount to keep the temperature below 30 ° C. The reaction under magnetic stirring was left at room temperature overnight. Then the solvent was evaporated and the residue was used to use 9.4 / 0.6 Purified by silica gel chromatography with alkane / AcOEt as eluent. 0.300 g of product (yield: 16%); melting point: 81-82 t; TLC: silicone, eluent system 7/3 of hexane / AcOEt, Fr: 0.45; 1H NMR (CDCU, 300MHz) 5 8.25 (d, 2H), 7.80 (d, 2H), 7.30 (m, 1 Η), 7.05 (m, 1 H), 7.03 (m, 1 Η), 7.01 ( m, 1 Η) 6.90 (d, 1 H) »6.60 (d, 1 1), 5.10 (s, 2H), 3.70 (s, 3H), [50 (s, 6Η); HPLC • Column: Symmetry -C18 (5 microns ) CH3CN / H20, pH: constant, flow rate 〇85ml / min, 205mm 4.6x250mm, room temperature, mobile phase 85/15 (volume / volume) micron UV detector, residence time 6 · 2 4 minutes; C22H21NO6S was determined by elemental analysis. Example 2 2 [3- [chlorophenyl) ethoxy] phenylsulfide]-2-methylpropionate 丄 · ST25 1 8 According to the general formula A The title product was prepared as described in Step 2 as a solution of ST2195 (prepared as described in Example 17) (0.150 g, 0.41 mmol) in 9 -36- (31) (31) 200305410 ml of methanol. Initially, 4 ml of 1 equivalent of NaOH was added to it. The solution thus obtained was left under agitation and at room temperature for 48 hours. The solution was then diluted with water, acidified and the aqueous phase was extracted with AcOEt. The organic phase was dried over anhydrous Na2S04 and filtered, and the solvent was evaporated in vacuo. Obtained 0.128 g of product (yield = 88%): melting point: 1 05-1 06 ° C; TLC: silicone, eluent CHCI3 / CH3OH of 9.4 / 0.6, Fr: 0.42; 1H NMR (CDCI3, 300MHz) 5 7.45 ( m, 5H), 7.10 (m, 2H), 6.80 (dd, 1H), 4.15 (t, 2H), 3.05 (t, 2H) »1.50 (s, 6H); HPLC ·· column ·· Symmetry-C18 (5 microns) 4.6x250 mm, room temperature, mobile phase is 35 mg / volume (volume / volume) CH3CN / ammonium acetate with a molecular weight of 35 mg / volume, pH: constant, flow rate: 0.80 ml / min, 205 nm UV detection Tester, staying time 4.66 minutes; C18H19CI03S was determined by elemental analysis. Example 2 3 2-[— J-(2- (2,4-dichlorophenyl) ethylargonyl) phenylthio] isobutyrate methyl ester (ST2531) Preparation of the title according to the procedure described in Method B The product was methyl 2- (4-hydroxyphenylthio) isobutyrate (S T1 9 2 3, prepared as described in Example 1) (0.280 g, 1.24 mmol) and dissolved in 3 ml of anhydrous THF DIAD (0.325 g, 1.61 mmol) was added, and 2,4-dichlorophenylethanol-37- (32) (32) 200305410 (0.260) was added dropwise at 4 ° C at 0 ° C. G, 1.36 mmol) and triphenylphosphine (0.42 2 g, L 6 mmol). The reaction mixture under magnetic stirring was left at room temperature overnight. The solvent was then evaporated and the residue was purified by silica gel layer separation using 9.6 / 0.4 hexane / AcOEt as the eluent. 0.346 g of product (yield: 70%): melting point: 73-74 ° C; TLC: silicone, eluent 9/1 hexane / AcOEt, Fr: 0.26; 1 H NMR (CDCI3, 300MHz) 5 7.35 ( m, 3H), 7.22 (m, 2H), 6.83 (d, 2H), 4-18 (t, 2H) ^ 3.65 (s, 3H), 3.20 (t, 2H), 1.45 (s, 6H); HPLC: tube Column · Inertisil ODS-3 (5 micron) 4.6x250 mm, room temperature, mobile phase 85/15 (volume / volume) CH3CN / H20, pH: constant, flow rate: 1 ml / min, 205 nm UV Detector, dwell time 12.58 minutes; KF: 0.4% Η20; elemental analysis to determine C19H20CI2O3S 〇 Example 24 2-ί 3- (2- (2,4-dichlorobenzene) ethoxy) phenylthio] Preparation of Isobutyl Methyl Ester (ST2534) The title product was prepared according to the procedure described in Method B as 2- (3-hydroxyphenylthio) isobutyric acid methyl ester (ST2047, prepared as described in Example 3) ( 0.280 grams, 1.24 millimoles) and DIAD (0.325 grams, 1.61 millimoles) dissolved in 3 mL of anhydrous THF, and 2,4-bis in 4 mL of anhydrous THF was added dropwise at 0 ° C. Chlorophenyl alcohol (0.260 g, 1.36 mmol) and triphenylphosphine (0.422 g, -38- (33) (33) 200305410 1.61 mmol). The reaction under magnetic stirring was left at room temperature overnight. The solvent was then evaporated and the residue was purified by silica gel layer separation using 9.6 / 0.4 hexane / AcOEt as the eluent. 0.327 g of an oily product was obtained (yield 66%); TLC: silicone, eluent 9/1 hexane / AcOEt, Fr: 0.34; 1H NMR (CDCI3, 300MHz) 5 7.40 (d, 1 H), 7.20 (m, 3H), 7.00 (m, 2H), 6.90 (dd, 1H), 4.15 (t, 2H), 3.65 (s, 3H), 3.20 (t, 2H), 1.45 (s, 6H); HPLC : Column: Inertisil ODS-3 (5 microns) 4-6x250 mm, room temperature, mobile phase 90/10 (volume / volume) CH3CN / H2〇, pH: constant 'Flow rate: 0.8 ml / min, 205 nm UV detector, dwell time of 12.40 minutes; KF: 0.2% Η20; C19H20CI2O3S determined by elemental analysis ○ Example 25 2-carbazole-9-yl) ethyl gas] benzenesulfur] butyl butyl methyl acetate (ST2365 ) Preparation The title product was prepared according to the procedure described in Method B, and 2- (3-hydroxyphenylthio) isobutyric acid in 14 ml of anhydrous THF was added in a small amount to maintain the temperature below 30 ° C. Methyl ester (ST204, prepared as described in Example 3) (0.609 g, 2.7 mmol), 9'-carbazole-9-ethanol (0.507 g, 2.7 mmol), DIAD (0.708 g, 3.5 Millimolar) and triphenylphosphine (0 · 91 7 grams, 3.5 millimoles). The reaction mixture under magnetic stirring was left at room temperature for 18 hours. The -39- (34) (34) 200305410 solvent was then evaporated to dryness and the residue was purified by silica gel chromatography using 9/1 hexane / AcOEt as the eluent. Obtained 0.510 g of product (yield: 45%): melting point: 10 1 -1 0 ° C; TLC: silicone, eluent 8/2 hexane / AcOEt, Fr: 0.38; 1 H NMR (CDCI3, 300MHz) δ 8.0 5 (d, 2H), 7.50 (m, 4H), 7.15 (m, 2H), 7.08 (t, 1 H), 7.00 (d, 1 H) »6.90 ( s, 1 H), 6.80 (m, 1 H), 4.75 (t, 2H), 4.35 (t, 2H), 3_60 (s, 3H), 1.40 (s, 6H); HPLC: column: Symmetry-C18 (5 microns) 4.6x 1 50 mm, room temperature, mobile phase 65/35 (vol / vol) CH3CN / H20, pH: constant, flow rate: 0.80 ml / min, 205 nm UV detector, stay Time 11.45 minutes; C25H25N03S was determined by elemental analysis. Example 26 1 2 "... 4- (2 dicarbazole-9-some) ethyl gas some] phenylthio] isobutyric acid methyl I _i ST 2 3 8 7) Preparation according to the procedure described in Method B The title product was methyl 2- (cardiohydroxyphenylthio) isobutyrate (ST1 923, prepared as described in Example 1) (0.609 g, 2.7 mmol), 9H · carbazole-9-ethanol ( 0.507 grams, 2.7 millimoles), DIAD (0.708 grams, 3.5 millimoles), triphenylphosphine (0.917 grams' 3.5 millimoles) in 14 mL of anhydrous THF to keep the temperature below 3CTC Add it in small amounts. The reaction mixture was left at room temperature under magnetic stirring for 18 hours. Then the solvent was evaporated and the residue was purified by silica gel chromatography using a 9/1 hexane / AcOEt -40- (35) 200305410 agent 15 35 9 per meter of material as a dissolving agent. Obtained 0.702 grams of production (yield: 62%): melting point: 72-74 ° C; TLC: silicone, 8/2 hexane / AcOEt, Fr: 0.30; 1H NMR (CDCI3 300MHz) 5 8.05 (d, 2H ), 7.50 (m, 4H), 7_ (m, 4H), 6.75 (d, 2H), 4.75 (t, 2H), 4.

(t, 2H), 3.60 (s, 3H), 1.40 (s, 6H); HPLC column: Symmetry-Ci8 (5 microns) 4.6x150 mm, room temperature mobile phase 70/30 (vol / vol) CH3CN / H20, pH: change, flow rate: 0.80 ml / min, 205 nm UV detector, retention time 11.60 minutes; C25H25N03S was determined by elemental analysis. Example 2 7 An aortic contraction was performed on a Wistar male rat weighing 100-120 grams with a 12 / 12-hour daylight / dark cycle at a temperature of 21 ± 1 ° C and a humidity of 50 ± 15% And a cage with 15-20 gas changes per hour holds 5 animals (cage size: 425 mm x 266 mm x 180 mm, with sawdust). Animals were fed with LP ALTR0MIN (REIPER) and free water intake. Cardiac hypertrophy is induced by the use of a clamp (0.8 mm diameter) placed in the abdominal aorta between the diaphragm and the renal branch to constrict the abdominal aorta in Nembutal (pentabarbital i Pentobarbital sodium -41-(36) (36) 200305410 Induced left ventricular hypertrophy in anesthetized rats, and then used a group of animals as a control group, which suffered the same operation, but a group without implanted clips and therefore Will not suffer aortic contraction (blank group). Animals are therefore arbitrarily divided into the following groups: Blank group: operated on mice without aortic contraction (8 animals) Control group: operated on mice with aortic contraction (8 animals) CLO group: Operated on mice treated with the compounds described in the present invention for 12 weeks after aortic contraction and self-operation (11 animals) Evaluation of cardiac function The aorta was inserted into the left ventricle and connected to a pressure transmitter (Statham p23XL) and an amplifier (Biomedica Mangoni bm 61) using a polyethylene cannula. It was evaluated in elderly patients anesthetized with nembutu (sodium pentobarbital). Cardiac function during recording. The recorded parameters are: heart rate, left ventricular systolic and diastolic blood pressure, and positive and negative derivatives of ventricular pressure recorded on a personal computer with a special data acquisition system (IDAS) method. Performed for 30 minutes Macroscopic assessment At the end of the experiment, at the end of the experiment, the animals were sacrificed in a lethal dose of Nembutor, the abdominal cavity was removed and the internal organs were removed to confirm the correct application of the aortic clip, and the heart, lungs and liver were removed. After checking for possible abnormalities, thoroughly dry and weigh. The preliminary results obtained in this test show that the compound -42- (37) (37) 200305410 according to the present invention has good resistance in the treatment group compared with the control group. Drug properties and normalize blood pressure. Example 2 8 Evaluation of P PAR α ligand agonist activity with eukaryotic cells transiently transfected for transactivation assay in eukaryotic cells allows quantitative evaluation of theoretical ligands to promote The ability of a transcription factor to interact with its response elements in a promoter. Peroxisome proliferators activate receptor isoform a (PPARa) via 9-cis The heterogeneous dimerization of the luteinic acid receptor (RXR) suppresses the transcription of the target gene. If activated only in the presence of a ligand of at least one of the two receptors, the dimer formed can interact with The peroxisome proliferator-reactive element (PPRE) binding in the target gene promoter is combined. The transactivation assay therefore requires: a) a sufficient amount of PPAR α; b) a sufficient amount of 9-cis retinoic acid Receptor (RXR) amount; c) Chimeric plastids including receptor genes controlled by PPRE located upstream of heterophasic virus promoters. In our case, the recipient gene was chloramphenicol-acetamyltransferase (CAT) 〇PPAR α and RXR endogenous 値 are not sufficient at any time, so they can be passed to include the relevant receptor genes Exogenous supplementation that expresses the transfection effect of the vector. -43- (38) (38) 200305410 Plastid pCH1 1 0 includes the / 3-galactosidase gene and is co-transfected with the receptor gene C AT, so it provides internal control of transfection efficiency and results standardization. Experimental procedure A monkey kidney fibroblast (COS-7) cell line was used. The cells were transfected with the expression genes of the recipient gene (see item c above) and the coding sequence (c D N A) including the PPARa gene. Cells were exposed to increasing concentrations of inquiring compounds and evaluated for CAT activity. Untreated cells were used as the control group. An increase in C AT 値 indicates activation of PPAR α-dependent gene transcription (the agonist activity of the compound) in a manner that it binds to p p R E. Cell culture According to common cell culture techniques, 3.7 g / L of sodium bicarbonate, 4 mg of molecular weight L-glutamine, 4.5 g / L at 37 ° C and 5% vol / vol of carbon dioxide gas are used. Liters of glucose, 1 mg of molecular weight sodium pyruvate and 10% vol / vol fetal bovine blood corpuscle modified growth medium DMEM (Du 丨 be's modified eagle medium) at 100 μg / ml streptomycin And finally, monkey kidney fibroblasts (COS-7) were cultured in the presence of 100 U / ml of penicillin. COS-7 fine vortex transfection The COS-7 fine-44- (39) (39) 200305410 cells were transiently transfected by the co-precipitation technique of nucleic acid and calcium phosphate. Prior to transfection, cells were covered at a density of 3 x 105 cells / well on a flat plate having a diameter of 25 mm in diameter for 6 wells for 24 hours. Before transfection, the culture medium was changed for 2 hours, and then 280 microliters of the transfection mixture prepared as follows was added dropwise to each well: 1) the performance plastid of cDNA including PPARa (2.5 micrograms) 2) included Receptor gene CAT plastid (5 μg) 3) pCH1 1 0 (1 μg); + 17.5 μl of 2 g molecular weight calcium chloride. Fill with water to a final volume of 140 μl. An equal volume of HBS solution 2xpH7.1 (16 grams of sodium chloride, 0.74 grams of potassium chloride, 0.27 grams of sodium hydrogen phosphate dehydrate, 2 grams of dextrose, 10 grams of Hepes) per liter was added to the plastid mixture. The cells were incubated at 37 ° C for 6 hours in a 5% volume / volume carbon dioxide gas. In 2 ml of fresh medium, the compound described according to the present invention and the reference compound, clobete, and 4-chloro-6- (2,3-dimethylaniline) -2-pyrimidinylthioacetic acid (WY_1 4,643) for 24 hours. Untreated cells were used as a negative control group. Radiopharmaceutical assessments of the therapeutic ability of protein extracts from treated and untreated cells affecting the transcription of the receptor gene, CAT. Preparation of progenitor protein extract and test of CAT activity After treatment, cells were washed twice with phosphate buffer (5 ml) -45- (40) (40) 200305410, and mechanically free in TEN buffer Medium (10 mg of PH8 molecular weight [hydroxymethyl] aminomethane, 1 mg of molecular weight ethylenediamine tetraacetic acid at pH 8 and 0.1 g of sodium chloride) were taken out. After centrifugation in an Eppendorf 5417R centrifuge (F453011 motor) at 4 ° C and 1,000 revolutions per minute (rpm) for 2 minutes, the cells were resuspended in 0.15 ml of buffer (pH 0.25 g molecular weight reference [hydroxyl Methyl] aminomethane-hydrochloric acid), and lysed by repeated freezing and thawing (three five-minute cycles). Centrifuge at 4 ° C for 15 minutes at maximum speed to remove insoluble cellular material, and recover the upper mash and use it for CAT activity test. The test for measuring CAT activity consists of having in a final volume of up to 100 microliters with water: 1) 50 microliters of protein cell extract (heated at 65 ° C for 10 minutes) 2) 10 microliters of n-butylamyl- Coenzyme A (3.5 mg / ml) 3) 5 μl [14C] Chloramphenicol (0.25 μCi). After incubation at 37 ° C for about 2 hours, the reaction was blocked by 2 volumes of xylene / 2,6,10,14 tetramethylpentadecane (a mixture of 1: 2 (vol / vol)). After extraction with this solvent, 150 microliters of the upper phase was added to 5 ml of scintillation liquid and analyzed by a / 3 counter (scintillation meter) to determine the content of [1 4C] butanyl chloramphenicol formed by the enzyme reaction. The test for measuring 5-galactosidase activity uses the cold-galactosidase activity for the corresponding gene coded in the plastid PC Η 1 10 as the CAT activity standard for transfection efficiency -46- (41) 200305410 Within the control. Evaluation of 20 microliters of protein extracts in the presence of "Z buffer" (10 mg molecular weight potassium chloride, 1 mg molecular weight magnesium chloride and 50 mg molecular weight / 3 · fluorenyl alcohol in phosphate buffer) (see above) ) Activity against 2 mg / ml matrix ONPG (0-nitrophenyl-D-galactopyranoside). After 15-120 minutes incubation at 37 ° C (depending on the rate at which the typical yellow color appears), the reaction was blocked with 200 microliters of 1 g molecular weight sodium carbonate. The samples were incubated at room temperature for 10 minutes and then analyzed spectrophotometrically to measure the absorbance at a wavelength of 420 nm (A420). The CAT assay for Θ-galactosidase activity was standardized using the following formula: C4 7 sample count per minute-blank sample count per minute, galactosidase (cold-gal) active unit * X CAT sample volume (50 μl) cold-galactosidase sample volume (20 μl ) 夂 0 X dilution factor incubation time (minutes) 1-galactosidase activity unit Example 2 9 Transfection of eukaryotic cells with transition pieces to evaluate the agonist activity of PPAR α ligand (丨 丨 method) Use another alternative The main difference between activation systems is that the receptor system is located on the DNA and depends on how the ligand binding event is translated into a transcriptionally active role. -47- (42) (42) 200305410 In this mode, eukaryotic cells are encoded by a fusion protein between the DNA binding region (DBD) of yeast Ga 14 transcription factor and the ligand binding region (LBD) of PPAR α. The expression vector (Gal4DBD / PPARaLBD) was transiently transfected. Co-transfection includes five replication pairs with high affinity binding sites (called UAS, upstream activating sequences) upstream of Gal4, a strong viral promoter linked to the receptor gene chloramphenicol acetamyltransferase (CAT) Body carrier. This mode offers some advantages, the most important being that it is not interfered by endogenous receptors. In addition to expression and receptor vectors, cells were transfected with encoding; PCH1 10, a control vector for 3-galactosidase, to correct for differences in transfection efficiency. Experimental procedure Monkey kidney fibroblast cell line (COS-7) was used. The cells were co-transfected with a plastid carrying a gene receptor, a plastid encoding a fusion protein (Gal4DBD / PPARa LBD), and a control vector PCH110. Cells were then treated with increasing concentrations of the test compound and CAT activity was measured. Untreated cells were used as the control group. Cell culture in monkeys. Monkey kidney fibroblasts (COS-7) were cultured in the presence of 100 μg / ml streptomycin and finally 100 U / ml penicillin with 3.7 g / L sodium bicarbonate and 4 mg L-glutamine. Lamine, 4.5 g / L glucose, 1 mg molecular weight sodium pyruvate, and 10% vol / vol -48- (43) (43) 200305410 DMEM supplemented with DMEM (Dubeck's Modified Eagle Medium) China grows routinely. Transfection of COS-7 cell vortex transfection COS-7 cells were transiently transfected with FUGENE6 transfection reagents, which consisted mainly of multiple recombinant lipids, which were complexed with the carrier DNA during transfection. Cells were seeded in 12 well flat plates at 1.2 x 105 cells / well and cultured overnight at 37 ° C in 5% (volume / volume) carbon dioxide gas. Two hours after transfection, the culture medium was replaced with fresh serine-free media and then transfected with FUGENE6 transfection reagent according to the manufacturer's instructions. In brief, a transfection mixture comprising (per well) 0.8 microliters of performance vector, 1.6 microliters of receptor vector, 0.8 microliters of control vector, and 9 microliters of FUGENE6 transfection reagent was directly added in the presence of serine Under the cells. After 5 hours, the transfection medium was replaced with 1 ml of complete culture medium with or without 3 different concentrations of test compounds (2, 20, and 100 microgram molecular weight). As the positive control group, 2 microgram molecular weight Wy-14,643 (known PPAR alpha ligand) was used. Preparation of cell protein extract and CAT assay after 48 hours, cells were washed twice with 1 ml of phosphate buffered saline (PBS), and then 10 mg in TEN buffer (p Η 8-10) Molecular weight: [hydroxymethyl] aminomethane, 1 mg molecular weight of ethylene diamine tetraacetic acid ρΗ8, 0.1% molecular weight of sodium chloride). After centrifugation at room temperature at 1,000 revolutions per minute for 3 minutes at -49- (44) (44) 200305410, the cells were resuspended in 60 microliters of lysis buffer (0.25 g molecular weight Tris- HCI) and lysed in three rapid freeze / thaw cycles (three 5 minute cycles). Centrifugation was then performed at 4 ° C for 1 minute at 15,000 revolutions per minute (rpm) to remove cell debris. Glycerin (final 10% vol / vol) and / 9-fluorenyl ethanol (final 5 mg molecular weight) were then added, and cell extracts were stored at -80 ° C until assayed. The CAT activity test was performed as follows: 20 microliters of cell lysate (preheated at 65 ° C for 10 minutes to deactivate the endophosphorylase enzyme activity) was added to 10 microliters of n-butylfluorenyl-CoA (3-5 mg / Ml), 5 μl (0.25 μCi) [14C] chloramphenicol and 65 μl distilled water, and incubated at 37 t for 2 hours. The reaction was blocked with 200 microliters of xylene / 2,6,10,14 tetramethylpentadecane (in a 1: 2 (v / v) mixture) solution. After vigorous vortexing and centrifugation at maximum speed for 5 minutes, 150 microliters of the upper rhenium liquid phase was transferred to a scintillation vial in the presence of 5 ml of scintillation liquid and the relative radioactivity was measured with a / 3 counter. Test for determination of Θ-galactosidase pickling activity Cold-galactosidase activity was measured as follows: 20 microliters of cell extract was added to 1 volume of 2 mg / ml of 0NPG and 3 volumes of "Z buffer" ( In 7 50 microliters of reaction buffer consisting of 10 mg of molecular weight potassium chloride, 1 mg of molecular weight chloride and 50 mg of molecular weight / 3- sulfoethanol in phosphate buffered saline. The reaction was carried out at 37 ° C, and when a little typical yellow appeared, the molecular weight of 1 g of 200 microliters was added -50- (45) 200305410

Na2C03 blocked the reaction. The samples were incubated at room temperature for 10 minutes and then the absorbance (A42Q) at 420 nm was measured spectrophotometrically. The CAT activity results were normalized as / 5-galactosidase activity as follows: Counts per minute-blank samples count per minute yS-galactosidase activity unit cold-galactosidase activity unit ^ 420: Dilution incubation time (minutes) The preliminary results obtained (reported in Table 1) show that the compounds according to the invention are PPAR alpha agonists. Table 1 Compound 2 microgram molecular weight 20 microgram molecular weight 100 microgram molecular weight Example 5 1 50% 3 91.2% 1 3 7 2% (ST1983) Example 14 9 8.1% 3 60% 462.7% (ST2167) Example 24 113.1% 2 8 4.9 % 4 2 1% (ST2534) CAT receptor gene activation is compared with the result measured by the test compound (WY-1 4.463, 2 microgram molecular weight) (conventionally expressed as 100%). Percentage. Example 3 0 Increased HDL in db / db mice-Zengguzui-51-(46) (46) 200305410 In this experiment, db / db mice were used, where PPARa performance was above the standard performance (Memon et al. Human Endocrinology 2000, 4021-4031) and a substantial assessment of HDL-cholesterol 値 (Silver et al. J. Biol. Chem 1.999, 2 7 4:41 40-41 46) 〇 C57BL / KsJ db / db mouse warp 1 Adapted to standard conditions (22 ± 20 ° C; 55 ± 15% humidity; 15-20 times gas replacement / hour; 12-hour daylight / 12-hour dark cycle from 7 am to 7 pm), Provides standard 4 RF21 food (Mucedola). Blood samples were obtained from the tail vein with the aid of a Jelco 22G cannula (Johnson and Johnson) in the state after absorption (fasting from 8.30 am to 4.30 pm). Glucose, insulin, triglycerides, cholesterol, free amino acids, and urea 中 were examined in the plasma of evenly distributed mice in the treatment group. At the beginning of treatment, the animals are checked for weight and arrangements are made to monitor their water and food consumption. Mice were treated orally twice daily (at 8.30 am and 6.30 pm) for 10 or 14 days. The test compound (ST1 929) obtained as described in Example 4 was administered at a dose of 24 mg / kg in a vehicle of 10 ml / kg (including 1% CMC of 0.5% Tween in deionized H20). . Other test compounds were also administered at a dose equal to that of Example 4. Ciprofibrate (which is a known PPARa agonist) (Varanasi et al. J. Biol. Chem., 1996, 271: 2147-2155; Latruff et al. Cell Biochem. -52- ( 47) (47) 200305410

Biophys., 2000, 32 Spring: 21 3-220) at a dose of 20 mg / kg (Toxicol Pathol 1989 '17: 16-26 by Dwivedi et al .; Proc Natl Acad Sci USA 1 999 by Qi et al., 96: 1 585-1 590) ° The animals in the state of absorption were sacrificed 7 hours after the final treatment (fasted from 9.30 am to 4.30 pm). Determination of many lipid 値 and carbohydrate metabolism parameters important in blood 淸. Phosphotungstic acid-based precipitation reagent (ABX diagnostic agent) for treatment of blood pupa (to remove chylomicrons, very low-density and low-density lipoproteins) and cholesterol kit (ABX diagnostic agent) for assistance and Cobas Mira S autoanalyzer (Roche) was used to measure ηDL-cholesterol in the upper mash to measure HDL-cholesterol. The results show that the compounds according to the present invention are able to raise HDL-cholesterol 一样 in db / db mice in a similar manner to the same or higher 参考 than the reference compound (ciprobate) (Table 2). -53- (48) 200305410 Table 2 Increased HDL · cholesterol 値 compound dose (mg / kg) in db / db mice Treatment period (days) HDL-cholesterol 値 (%) Cyclopentil 20 14 + 52A Example 4 Compound 24 10 + 80A (ST1929) Example 8 Compound equals 24 mg 10 + 51 ▲ (ST2013) ST1929 Students, t,-Test: ▲ i represents p < relative to the control group 0.001. The compounds of formula (丨) described in accordance with the present invention may be used as they are or in pharmaceutically acceptable derivative forms (such as salts or derivatives) 'in order to improve the pharmacokinetic perspective while maintaining specific activity (formerly Body drugs). From the industrial point of view of the present invention of interest, pharmaceuticals will have suitable pharmaceutical formulation (or composition) dosage forms prepared by experts familiar with the art according to conventional methods. Examples of pharmaceutical compositions are tablets, capsules, medicines, suppositories, pouches, liquid dosage forms for oral administration (such as solutions, suspensions and emulsions), controlled release dosage forms usually administered orally or enterally, and parenteral Type (such as an injection). -54-

Claims (1)

(1) (1) 200305410 Patent application scope 1. A compound of formula (I) (I) where: R represents -H, -YCR5R6COX, monocyclic, bicyclic or tricyclic aryl or heteroaryl (it is possible to use -YCR5R6COX, halogen, nitro, meridian, alkyl, and possibly Halogen-substituted alkoxy type group substitution), monocyclic, bicyclic or tricyclic aralkyl or heteroaralkyl (where it is possible to replace aryl or heteroaryl with -YCR5R6COX, halogen, nitro, hydroxyl , The radical and the alkoxy type group which may be substituted by halogen), the heteroaryl group may be charged, as shown in the following formula: The positive charge is balanced by a suitable negative counter ion; m represents 0 -1; η represents 0-3; when η represents 1, R3 and R4 may be the same or different, and are selected from fluorene or alkyl CrCs; when η When it represents 2 or 3, J R3 is the same as R4 and represents Η; P represents 〇-1; X represents -0Η, · 0-alkyl Ci-Cs; -55- (2) 200305410 R1 and R2 can be g Identical or not, selected from ... _h; alkyl I. C5, alkoxy groups that can be substituted with halogen; phenoxy groups that may be substituted with halogen, nitro, hydroxyl, and alkyl; possible with halogen , Hydroxy, alkyl-substituted carboxy cox; or together with c0x of the general formula (丨) to form a ring of the following type: ά 'Λ〇〇R5 and R6 may be the same or different, and are selected from the groups defined by Ri and R2; Q and Z may be the same or different, and are selected from: | ^ | _ |, 〇, 3,- NHC (0) 0-, NHC (〇) NH-, -NHC (0) S-, -OC (0) NH- > -NHC (S) 〇-, -NHC (S) NH- > -C (O) NH-; and Ya represent 0, S. 2. The compound of formula (i) according to item 1 of the scope of patent application, which is used in the medical field. 3. A pharmaceutical composition comprising, as its active ingredient, a compound of formula (|) according to item 1 of the scope of patent application and at least one pharmaceutically acceptable excipient and / or diluent. 4. The pharmaceutical composition according to item 3 of the scope of patent application, which is in the form of tablets, capsules, medicines, medicine bags, vials, powders, suppositories, solutions, suspensions, emulsions or liposome preparations. -56- (3) 200305410 5 · The pharmaceutical composition according to item 4 of the scope of patent application 'can be administered by enteral or parenteral route. 6.-Use of a compound of formula (I) according to item 1 of the scope of patent application, which is used for the preparation of a medicament for treating a disease that responds to the activation of P PAR α. 7. Use according to item 6 of the patent application, wherein the disease is selected from the group consisting of heart failure, hyperlipidemia, and atherosclerosis. -57- 200305410 Lu, (a), the designated representative of this case is: Figure _ (b), the component representative symbols of this representative are simply explained: None 柒 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: The designated chemical formula in this case is: 丄 Chemical formula